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Original research
Pathophysiological insights into machine learning-based subphenotypes of acute heart failure with preserved ejection fraction
  1. Yohei Sotomi1,
  2. Shunsuke Tamaki2,
  3. Shungo Hikoso1,
  4. Daisaku Nakatani1,
  5. Katsuki Okada1,3,
  6. Tomoharu Dohi1,
  7. Akihiro Sunaga1,
  8. Hirota Kida1,
  9. Taiki Sato1,
  10. Yuki Matsuoka1,
  11. Daisuke Sakamoto1,
  12. Tetsuhisa Kitamura4,
  13. Sho Komukai5,
  14. Masahiro Seo6,
  15. Masamichi Yano7,
  16. Takaharu Hayashi8,
  17. Akito Nakagawa1,3,9,
  18. Yusuke Nakagawa10,
  19. Tomohito Ohtani1,
  20. Yoshio Yasumura9,
  21. Takahisa Yamada6,
  22. Yasushi Sakata1
  23. on behalf of the OCVC-Heart Failure Investigators
    1. 1 Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan
    2. 2 Department of Cardiology, Rinku General Medical Center, Izumisano, Japan
    3. 3 Department of Medical Informatics, Osaka University Graduate School of Medicine, Suita, Japan
    4. 4 Department of Social and Environmental Medicine, Osaka University Graduate School of Medicine, Suita, Japan
    5. 5 Division of Biomedical Statistics, Department of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan
    6. 6 Division of Cardiology, Osaka General Medical Center, Osaka, Japan
    7. 7 Division of Cardiology, Osaka Rosai Hospital, Sakai, Japan
    8. 8 Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
    9. 9 Division of Cardiology, Amagasaki Chuo Hospital, Amagasaki, Japan
    10. 10 Division of Cardiology, Kawanishi City Medical Center, Kawanishi, Japan
    1. Correspondence to Dr Shungo Hikoso, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; hikoso{at}cardiology.med.osaka-u.ac.jp

    Abstract

    Objective The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology.

    Methods This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated.

    Results Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15.

    Conclusions Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy.

    Trial registration number UMIN-CTR ID: UMIN000021831.

    • heart failure
    • heart failure, diastolic
    • biomarkers

    Data availability statement

    No data are available. Our study data will not be made available to other researchers for purposes of reproducing the results because of institutional review board restrictions.

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    Data availability statement

    No data are available. Our study data will not be made available to other researchers for purposes of reproducing the results because of institutional review board restrictions.

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    Footnotes

    • YS and ST contributed equally.

    • Collaborators Tetsuya Watanabe, Osaka General Medical Center, Osaka, Japan; Yoshiharu Higuchi, Osaka Police Hospital, Osaka, Japan; Masaharu Masuda, Mitsutoshi Asai and Toshiaki Mano, Kansai Rosai Hospital, Amagasaki, Japan; Hisakazu Fuji, Kobe Ekisaikai Hospital, Kobe, Japan; Daisaku Masuda, Ryu Shutta and Shizuya Yamashita, Rinku General Medical Center, Izumisano, Japan; Masami Sairyo, Kawanichi City Medical Center, Kawanishi, Japan; Haruhiko Abe, Yasunori Ueda and Yasushi Matsumura, National Hospital Organization Osaka National Hospital, Osaka, Japan; Kunihiko Nagai, Ikeda Municipal Hospital, Ikeda, Japan; Masami Nishino and Jun Tanouchi, Osaka Rosai Hospital, Sakai, Japan; Yoh Arita and Nobuyuki Ogasawara, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan; Takamaru Ishizu, Minoru Ichikawa and Yuzuru Takano, Higashiosaka City Medical Center, Higashiosaka, Japan; Eisai Rin, Kawachi General Hospital, Higashiosaka, Japan; Yukinori Shinoda, Koichi Tachibana and Shiro Hoshida, Yao Municipal Hospital, Yao, Japan; Masahiro Izumi, Kinki Central Hospital, Itami, Japan; Hiroyoshi Yamamoto and Hiroyasu Kato, Japan Community Health Care Organization, Osaka Minato Central Hospital, Osaka, Japan; Kazuhiro Nakatani and Yuji Yasuga, Sumitomo Hospital, Osaka, Japan; Mayu Nishio and Keiji Hirooka, Saiseikai Senri Hospital, Suita, Japan; Takahiro Yoshimura, Kazunori Kashiwase and Shinji Hasegawa, National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Japan; Akihiro Tani, Kano General Hospital, Osaka, Japan; Yasushi Okumoto, Kinan Hospital, Tanabe, Japan; Yasunaka Makino, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan; Toshinari Onishi and Katsuomi Iwakura, Sakurabashi Watanabe Hospital, Osaka, Japan; Yoshiyuki Kijima, Japan Community Health Care Organization, Hoshigaoka Medical Center, Hirakata, Japan; Takashi Kitao, Minoh City Hospital, Minoh, Japan; Masashi Fujita, Osaka International Cancer Institute, Osaka, Japan; Koichiro Harada, Suita Municipal Hospital, Suita, Japan; Masahiro Kumada and Osamu Nakagawa, Toyonaka Municipal Hospital, Toyonaka, Japan; Ryo Araki and Takayuki Yamada, Otemae Hospital, Osaka, Japan; Bolrathanak Oeun, Yasuhiro Akazawa, Kei Nakamoto, Fusako Sera, Hidetaka Kioka, Toshihiro Takeda, Hiroya Mizuno, Yasushi Sakata, Osaka University Graduate School of Medicine, Suita, Japan.

    • Contributors Concept and design—YSo, ST, SH, YY, TY and YSa. Data analysis and statistical analysis—YSo, ST and SH. Manuscript draft—YSo, ST, SH and YSa. Critical revision, editing and approval of the final manuscript—all authors. Guarantors—YSo, ST, SH and YSa.

    • Funding This work was funded by Roche Diagnostics and FUJIFILM Toyama Chemical Co.

    • Competing interests YSo has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical, TOA EIYO, Bristol-Myers Squibb, Biosense Webster, Abbott Medical Japan and NIPRO; and personal fees from Abiomed, AstraZeneca, Amgen Astellas BioPharma, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Abbott Medical Japan, Boston Scientific Japan, Bayer, Daiichi Sankyo, Novartis, TERUMO, Medtronic and Pfizer Pharmaceuticals. SH has received grants from Roche Diagnostics, FUJIFILM Toyama Chemical and Actelion Pharmaceuticals; and personal fees from Daiichi Sankyo, Astellas Pharma, Bayer, Pfizer Pharmaceuticals, Boehringer Ingelheim Japan, Kowa Company and Ono Pharmaceutical. DN has received personal fees from Roche Diagnostics. YSa has received personal fees from Otsuka Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, AstraZeneca and Actelion Pharmaceuticals; and grants from Roche Diagnostic, FUJIFILM Toyama Chemical, Bristol-Myers Squibb Co, Biosense Webster, Abbott Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma, Kowa Company, Boehringer Ingelheim Japan and Biotronik.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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